Complex interactions between nerves and hormones regulate pancreatic exocrine secretion. Peptidergic neurones are an important component of the vagal, sympathetic, sensory and intrinsic innervation of the pancreas. The peptides are synthesized and transported by these nerves and serve as important neurotransmitters. Examination of the role of neuropeptides in the regulation of pancreatic exocrine secretion has been hampered because specific antagonists were not available. Although neuropeptides almost certainly participate in the enteropancreatic reflex, by which food in the intestine induces pancreatic secretion, the relative importance of neural and humoral pathways in this reflex is unknown because satisfactory models for complete extrinsic denervation were lacking. We now have specific antagonists for neuropeptides and can successfully transplant the jejunum to achieve total extrinsic denervation. We propose, therefore, three specific aims which will elucidate the role of neuropeptides in the neural control of pancreatic exocrine secretion. Specific aim I examines the contribution of peptidergic neurones to the vagal control of pancreatic secretion by using specific antagonists to cholecystokinin, vasoactive intestinal polypeptide, gastrin releasing peptide and somatostatin; these peptides are contained in vagal as well as in intrinsic pancreatic neurones. Specific aim II examines the role of the sensory innervation of the pancreas in two ways. Firstly, low doses of the sensory neurotoxin, capsaicin, will be administered to the isolated, vascularly-perfused pancreas to release neuropeptides (calcitonin gene-related peptide and substance P) from sensory nerve fibers. Secondly, the sensory innervation of the pancreas will be ablated by the chronic administration of high doses of capsaicin. The consequences of these treatments to pancreatic exocrine secretion will be studies. Specific aim III examines the importance of enteropancreatic reflexes by small intestinal transplantation, a well- established technique in our laboratory. By this technique and by using specific antagonists of cholecystokinin, secretin, vasoactive intestinal polypeptide an gastrin releasing peptide we will be able to determine the mechanism by which intestinal nutrients stimulate pancreatic secretion. The proposed work has important application to our understanding of human pancreatic diseases and to their treatment by surgical intervention and transplantation.